Competition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller

Emily G. Saccuzzo, Mubark D. Mebrat, Hailee F. Scelsi, Minjoo Kim, Minh Thu Ma, Xinya Su, Shannon E. Hill, Elisa Rheaume, Renhao Li, Matthew P. Torres, James C. Gumbart, Wade D. Van Horn () and Raquel L. Lieberman ()
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Emily G. Saccuzzo: Georgia Institute of Technology
Mubark D. Mebrat: Arizona State University
Hailee F. Scelsi: Georgia Institute of Technology
Minjoo Kim: Arizona State University
Minh Thu Ma: Georgia Institute of Technology
Xinya Su: Georgia Institute of Technology
Shannon E. Hill: Georgia Institute of Technology
Elisa Rheaume: Interdisciplinary Graduate Program in Quantitative Biosciences, Georgia Institute of Technology
Renhao Li: Emory University School of Medicine
Matthew P. Torres: Georgia Institute of Technology
James C. Gumbart: Georgia Institute of Technology
Wade D. Van Horn: Arizona State University
Raquel L. Lieberman: Georgia Institute of Technology

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Studies of folded-to-misfolded transitions using model protein systems reveal a range of unfolding needed for exposure of amyloid-prone regions for subsequent fibrillization. Here, we probe the relationship between unfolding and aggregation for glaucoma-associated myocilin. Mutations within the olfactomedin domain of myocilin (OLF) cause a gain-of-function, namely cytotoxic intracellular aggregation, which hastens disease progression. Aggregation by wild-type OLF (OLFWT) competes with its chemical unfolding, but only below the threshold where OLF loses tertiary structure. Representative moderate (OLFD380A) and severe (OLFI499F) disease variants aggregate differently, with rates comparable to OLFWT in initial stages of unfolding, and variants adopt distinct partially folded structures seen along the OLFWT urea-unfolding pathway. Whether initiated with mutation or chemical perturbation, unfolding propagates outward to the propeller surface. In sum, for this large protein prone to amyloid formation, the requirement for a conformational change to promote amyloid fibrillization leads to direct competition between unfolding and aggregation.

Date: 2024
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DOI: 10.1038/s41467-023-44479-2

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